I cover cardiology news for CardioExchange, a social media website for cardiologists published by the New England Journal of Medicine. I was the editor of TheHeart.Org from its inception in 1999 until December 2008. Following the purchase of TheHeart.Org by WebMD in 2005, I became the editorial director of WebMD professional news, encompassing TheHeart.Org and Medscape Medical News. Prior to joining TheHeart.Org, I was a freelance medical journalist and wrote for a wide variety of medical and computer publications. In 1994-1995 I was a Knight Science Journalism Fellow at MIT. I have a PhD in English from SUNY Buffalo, and I drove a taxicab in New York City before embarking on a career in medical journalism. You can follow me on Twitter at: @cardiobrief.

How Heart Guidelines Based On Disgraced Research May Have Caused Thousands Of Deaths

What if doctors kept prescribing drugs based on large clinical trials that had been discredited? That is exactly what is happening in Europe, as guidelines for physicians have remained unchanged even as the studies they are based on were caught up in a two-year-old scandal. Some researchers say thousands of patients may have died as a result in the United Kingdom alone.

Don Poldermans

Current European Society of Cardiology guidelines recommend that beta-blockers be given to many patients having surgery for noncardiac reasons to protect the heart during surgery. (US guidelines are somewhat less aggressive in their endorsement of perioperative beta-blockade.) The guidelines, which were published in 2009, were based on analyses of the available trials. The strongest evidence came from the DECREASE family of trials, which appeared to strongly support perioperative beta-blockade, and one other large trial, POISE, which raised concerns that beta-blockers might lead to an increase in deaths. When the ESC committee combined all the data they found a neutral effect on mortality but a strong benefit due to significant reductions in non-fatal MI and stroke with beta blocker use. This was the basis for the strong recommendation in the ESC guidelines.

In 2011, however, faith in the reliability of the DECREASE trials was shattered as a result of a scientific misconduct scandal centering on the principal investigator of the studies, the now disgraced Dutch researcher Don Poldermans. The issue was further complicated because, in addition to his key role in the trials, Poldermans was the chairman of the committee that drafted the guidelines.

Now, a group of UK researchers, led by Darrel Francis, have published in the journal Heart the results of a meta-analysis of the remaining non-DECREASE trials that tested perioperative beta-blockade. With the removal of the DECREASE trials the findings were strikingly different from the earlier analyses. In a combined population of 10,529 patients taken from 9 trials there was a statistically significant increase in the risk of death in the group of patients randomized to beta-blockers:

162 deaths in 5264 patients randomized to beta-blockeres versus 129 deaths in 5265 patients randomized to placebo, for a 27% increase in the risk of death (RR 1.27, CI 1.01- 1.60, p=0.04).

In sharp contrast, the two randomized placebo-controlled DECREASE studies resulted in a 58% reduction in mortality associated with beta-blockers (although this was not statistically significant).

The analysis did find some benefits associated with beta-blockade, including a statistically significant reduction in non-fatal MI. However, it also found a significant increase in hypotension and stroke. In the new meta-analysis any beneficial effects are clearly overshadowed by the most important finding of an increased risk in death.

Each year in the UK, according to the Heart authors, 2.5 million procedures are performed each year for which this treatment is recommended in the current guidelines. Based on a 27% increase in the risk of death associated with perioperative beta-blockade, they calculated that as many as 10,000 deaths might be caused by physicians faithfully following the guidelines. In an interview, Francis said that there is no way to reliably assess the true extent of the possible damage, either in the UK or elsewhere. The estimate of 10,000 deaths is based on the limited available data.

The UK authors concluded:

Patient safety being paramount, guidelines for perioperative β-blocker initiation should be retracted without further delay. Future guidelines should be accompanied by a commitment from named individuals to retract them immediately if the advice given is later revealed to be harmful.

Routine initiation of β-blockers for this indication should not be recommended, except in the context of RCTs which should be designed carefully, conducted honestly and reported truthfully.

Darrel Francis

The chair of the ESC Clinical Practice Guidelines Committee, Jose Luis Zamorano, said that the ESC is currently revising the guidelines, with a new version expected in the first months of 2014. He said the ESC was taking the meta-analysis “very seriously” and would “convene an urgent task force to decide whether further actions are required.”

The new meta-analysis is “interesting but not surprising,” said Sripal Bangalore, the author of a 2008 meta-analysis that raised early questions about both the European and US guidelines. He said the paper is concordant with the POISE trial and his own meta0analsysis. He said it was “difficult to prove” the estimates of the number of deaths that may have been caused by the guidelines.

Leslie David Hillis, the chair of the ACCF/AHA CABG guidelines, said that the Heart paper data and conclusions were “accurate” and that the findings were potentially important.

Sanjay Kaul said that he generally agreed with the conclusions of the Heart paper that the evidence does not support strong recommendations for perioperative beta blockade, but he said that “the mortality evidence against beta blockade is not robust.” In his own practice, he said, he does ”not initiate beta blockers to modify perioperative risk even in high-risk patients. I also do not hold beta blockers prior to surgery in those who are on them long term.”

Mariell Jessup, speaking on behalf of the American Heart Association, said that she thought “the issue of how we use beta blockers in the peripoperative period is very complex and probably requires more trials, irrespective of what we think of some of the trials in the past, and requires great care as we move forward.” She said this issue was now the subject of intense discussion by the joint ACCF/AHA guidelines committee.

Some defenders of perioperative beta-blockade have argued that although initiating beta-blockers on the same day as surgery may be dangerous, a slow and gradual introduction of the drugs for as long as 30 days before surgery may be beneficial. However, according to Francis, this strategy has never been tested in a clinical trial outside of the DECREASE family. In addition, even if this strategy proved safe, it would likely not be feasible in most cases, since perioperative beta-blockade falls under the purview of the anesthesiologist, who generally first sees the patient on the day of the procedure.

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Thanks for bringing forward this important issue Larry. Preoperative assessment of patients undergoing non-cardiac surgery is a common task among cardiologists. However, this is a difficult area and the literature is scarce. Therefore we rely heavily on clinical guidelines. We believe them to be the holy grail when it comes to these issues. If our recommendations are based on current clinical guidelines, we cant really be wrong, can we?

However, although guidelines may be helpful, their weakness is becoming increasingly apparent. The above is good example of this problem. Was it premature to recommend the use of beta blockers based on the DECREASE trials? It certainly appears so. What are the consequences? How is it going to be dealt with? How long is it going to take?

Of course the whole story also raises the issue of scientific misconduct in medicine. We have another recent example of that:

Thanks for this article, which explains the background issues and the current state of the research very well. I am surprised to find that so many physicians continue to use beta blockers despite the flaws and misconduct in the original studies.

There is a simple solution for the pharmaceutical industry to get trusted oversight that resonates with everyone and, at the same time, cuts cost. The CNN Gallup Poll has rated nurses, for 13 straight years, the #1 most trusted profession in America. Nurses have been the patients’ advocates for 150 years.

Start BY creating a worldwide-connected community of millions of nurses, who self-identify by specialty and other relevant characteristics…AT POINT OF CARE! A Nurse Portal could feature easy and intuitive sign-up, access and use for nurses via virtually any mobile device, tablet, laptop or pc. The simple, secure application has a nurse interface and a dashboard for industry customers, practitioners and other non-nurses. In that new hardware is not immediately needed, the “Nurse Portal” may be relatively simple to construct. Epocrates Inc. has demonstrated how physician feedback can be harnessed and valued, possibly making a nursing prototype redundant. But this is more… • A COST EFFECTIVE CLINICAL TRIAL RECRUITMENT VEHICLE’ that can reach nurses, dispersed throughout the world, at the patients’ bedsides and homes, and give them the ability to identify and explain life saving options to patients, when they are motivated to listen. This is indispensible when life-death decisions need to be made rapidly! Nurses will then notify clinical trial reps to sign up qualified candidates. With robust social media tools, nurses from premier academic and medical centers, can collaborate within, and across organizations to reach remote areas using; video conferencing, skype, translate, simulation labs etc.

• FACILITATES PARTICIPATORY DESIGN AND USABILITY TESTING, Drug companies can use customized surveys to: collect nursing insights on drugs and the patient experience as Epocrates Inc. does for doctors; and rate and improve health applications. Visiting nurses can: monitor the predictors of readmission; encourage patients and families to engage in health applications, and provide critical documentation necessary to make adjustment in the protocol to maximize the success of studies. Hospital beds/floors can be designated for clinical trial patients, with research nurses playing a vital role in ensuring oversight and that clinical studies run smoothly. The most advanced nurses should be at touch point with business innovators, contributing nursing expertise to protocol design, and driving innovation.

It is important to realize “nursing data” harnessed from medical records reflects information doctors and hospitals steer or ask the nurse to provide. Ironically, nursing expertise is aligned to give business a better understanding of the patient experience and create products consumers’ want and trust.

I am a nurse with no financial interest but really want this to happen.